It has become apparent that blood-borne and blood vessel bound factors play a major role in the propagation and persistence of a large number of diseases in many different fields of medicine. The growth of tumors, progression of arthritis, and propagation of atherosclerosis are but a few of the important clinical scenarios in which growth factor (GF) control has been demonstrated.
This control is presumed to stem from the basic dependence of these diseases, and others like them, on blood vessels for nourishment and support. The growth and replication of the endothelial cells that line the blood vessels and the smooth muscle cells that surround the blood vessels appears to be modulated by an expanding family of GFs. The growth factors that stimulate endothelial cells have a strong affinity for heparin. As such, the effects of heparin and heparin avid growth factors and their inhibitors are the subject of extensive study.
While heparin avid growth factors are highly potent, they tend to degrade rapidly and are currently in short supply. Thus, they cannot be ingested or injected and in vivo studies, if possible at all, are limited to only the most short term effects of minute quantities of factor.
The technology of controlled drug delivery provides an effective means of storing and delivering a wide variety of pharmaceuticals. Unfortunately, the development of a controlled release growth factor system has been hindered by a number of significant problems. Key among these are denaturation and loss of biological activity when such factors are stored for prolonged periods, as well as enhanced loss when exposed to the procedures of standard controlled release device (CRD) fabrication. For example, even if stored in the most concentrated formulations at optimum temperatures, over 90% of the biological activity of many growth factors is lost in four weeks.
In addition, conventional means of CRD encapsulation press or dissolve an encapsulating material around the pharmaceutical. This generally requires exposing a mixture of the pharmaceutical and the encapsulating material to an elevated temperature, pressure or ionic strength. Extremes of pH or contact with organic solvents might also be required. Each of these exposures is known to drastically denature growth factors.
Additionally, simply encapsulating microliter quantities of growth factors has proven problematic. It is exceedingly difficult to obtain uniform dispersion of such a small quantity of liquid within any of the conventional controlled release devices. Attempts to overcome this drawback by dilution with other liquids or lyophilization of the growth factors in combination with other powdered materials have enhanced the loss of biological activity.
Thus, a need exists for a method for preventing the denaturation and loss of bioactivity of growth factors when stored for prolonged periods. Additionally, a need exists for a controlled release device compatible with growth factors that would allow them to be released at a generally uniform, or at least predictable, rate over a period of time.